JP2001521798A - Apparatus and method for in vivo delivery of therapeutic agents - Google Patents

Abstract

(57) [Summary] Electroporation electrodes (12, 22) are laminated on a permeable membrane (11, 21) to form an electrode membrane. Such an electrode membrane is placed in direct contact with the skin and mucous membranes, and then, by applying electric field pulses at predetermined intervals, continuously controlled delivery of the therapeutic agent through the skin and mucous membranes. It is very effective. The electrode membrane can be configured such that the ion permeation electrode is incorporated in the same device. Such devices can be used for both electroporation and delivery of drugs by iontophoresis through the skin and mucous membranes.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to the delivery of therapeutic agents, and specifically to a method and apparatus for delivering therapeutic agents through skin and mucous membranes using electromotive force such as electroporation and iontophoresis. It is about.

BACKGROUND INFORMATION Electroporation includes electroosmosis, but in this method an aqueous solution path is formed in a lipid bilayer by applying a short electric field pulse. Electroporation is a technique used in the fields of molecular biology and gene transplantation to instantaneously charge a cell with a high voltage to give it DNA.
And other methods for introducing other substances. In recent years, this method has also been applied for the purpose of delivering a therapeutic agent into the living body through the skin or mucous membrane.
The electric field created by the positive or negative potential difference between the two electrodes causes pores in the skin and mucous membranes. These reversible pathways (pores) created using electroporation increase the membrane (skin, mucosa) permeability of the substance. But conventionally,
There was a problem in establishing a proper relationship between electrode placement and electrode position.

[0002] Furthermore, since multiple administrations require the use of electrodes and therapeutic agents many times,
Repeated application and removal of the electrodes resulted in inflammation of the site tissue. Also, in order to deliver the therapeutic agent over a long period of time or to apply a voltage many times, it was necessary to attach the electrode and the therapeutic agent many times. In making an actual device, it has been difficult to place the therapeutic agent on the surface of the electrode and arrange the surface containing the therapeutic agent and the surface of the electrode in direct contact with the skin. Thus, the problems of conventional devices using electroporation have not been solved.

[0003] It is known that the combined use of electroporation and iontophoresis can further enhance the penetration of therapeutic agents. Ion penetration therapy uses an electric current to activate and modulate the diffusion of charged molecules in biological membranes such as the skin. Such activation and modulation are performed in the same manner as passive diffusion with a concentration gradient,
The pace is faster. In general, iontophoresis uses an electrode pair for iontophoresis, an electrode for iontophoresis (anode or cathode), and a reverse electrode to pass electrical potential energy or current through a semipermeable barrier. In order to use electroporation and iontophoresis together, the electrodes for iontophoresis must be placed in the same compartment (in the same apparatus) as the electrode pair for electroporation. Although there are examples of in vivo experiments using both electroporation and iontophoresis, conventional techniques have not been able to create a device that can actually use both types of electrodes.

[0004] Accordingly, the present inventor has determined that it is desirable to provide a method or apparatus with the following capabilities not available with conventional techniques.

(1) The therapeutic agent is simply administered through the skin or mucous membrane using an electrode pair for electroporation.

(2) The electrode can be adhered over a long period of time and a voltage can be applied many times without repeatedly attaching and detaching the electrode.

(3) An electric field pulse for electroporation and a drug component containing a therapeutic agent can be simultaneously administered.

(4) An electrode for electroporation and an electrode for ion permeation can be used in combination. The present invention provides such capabilities.

Outline The permeable membrane is porous and is used for supporting an electrode for electroporation. An osmotic membrane is arranged so as to be in direct contact with skin and mucous membranes, and is provided with electric field pulses at predetermined intervals. Is also useful for the purpose of delivering the therapeutic agent through the skin or mucous membranes in a controlled amount almost continuously. An electrode for electroporation can be attached to this porous membrane to form an electrode membrane. Further, the electrode membrane can be configured so that the ion permeation method electrode is incorporated in the same device. Such an apparatus can be used for both electroporation and iontophoresis. Still further, devices with these types of electrode films are actually useful and easy to produce.

DETAILED DESCRIPTION The structure and operating parameters of a preferred embodiment of the present invention will be described below with reference to FIGS. 1 and 2. In these drawings, one embodiment of the present invention is shown. FIG. 1 is a side view of the device. FIG. 2 is a plan view of the same device as that shown in FIG. Drug permeable membranes 11, 21 (FIGS. 1 and 2 respectively)
Is preferably a porous membrane. The electrode pairs 12 for electroporation are provided on the drug permeable membranes 11 and 21.
, 22 are adhered, and the device of the first embodiment forms an electrode film. Although the illustrated contact electrode pairs 12 and 22 depict a pattern in which two comb-like electrodes are engaged with each other (however, the electrodes are not in contact with each other),
The invention is not limited to such a shape. Portions of the illustrated contact electrode pairs 12, 22 project from the membranes 11, 21. However, the contact electrode pairs 12, 22 may be completely embedded in the drug permeable membrane. This projection of the contact electrode pair is
Terminals for connecting the power supply devices 2 and 22 to a power supply device (not shown).

The material used for forming the membranes 11 and 21 supporting the contact electrode pairs 12 and 22 is not particularly limited, but the kind of the therapeutic agent to be administered or the pharmaceutical ingredient containing the therapeutic agent Can be selected (eg, by a heuristic method) depending on the nature of For example, when a water-soluble drug component or therapeutic drug is used, a hydrophilic membrane having no membrane permeation limit for the drug component is selected. When a lipid-soluble drug component or a therapeutic drug is used, it is preferable to use a hydrophobic membrane having no membrane permeation limit for the drug component. Similarly, it is preferred to use a porous membrane with pores that does not interfere with the delivery of the therapeutic agent or pharmaceutical ingredient being administered. The size of the pores is preferably about 0.01 mm to 10 mm, but in order to hold the drug component in the device, prevent leakage, and maintain the penetration rate of the drug through the membrane at a preferable value, It is more preferably about 0.1 mm to 5 mm. For example, materials used as membranes in various embodiments include nylon, polyvinylidene fluoride, cellulose, nitrocellulose, polycarbonate, polysulfone, polyethylene, polypropylene, nonwoven fabric, gauze, woven fabric, paper, cotton fabric, polyethylene foam, Examples include, but are not limited to, porous and foamed materials such as expanded polypropylene, expanded polyvinyl acetate, expanded polyolefin, expanded polyamide, and expanded polyurethane. Examples include such materials and their chemically modified or chemically processed products, but materials that fall within the scope of the present invention are not limited thereto.

Examples of a method of attaching the contact electrode pairs 12 and 22 to the support films 11 and 21 include, but are not limited to, bonding, printing, vapor deposition, and plating. Among these methods, printing is particularly preferred. Because printing is
This is because it can be easily controlled by a technique such as using a pattern or performing screen printing on a template. Adhesion is also preferable because of easy integration.

The contact electrode pairs 12 and 22 are a pair of an anode and a cathode, and are mounted on the permeable membranes 11 and 21. To increase the voltage efficiency, it is preferable to reduce the distance between the two electrodes. However, if so, a short circuit may occur in the films 11 and 21.
The distance varies depending on the method of mounting, taking into account factors such as the efficiency of electric pulse application, whether the mounting is easy, and the accuracy of the mounting. Generally, it is preferably about 10 mm to 1 cm, more preferably about 50 mm to 5 mm,
About 100 mm to 2 mm is more preferable.

The contact electrode pairs 12, 22 are made of a conductive material or conductive material such as carbon, platinum, gold, titanium, aluminum, nickel, steel, silver, silver chloride, copper, copper chloride, or an alloy of one of these. It is made of a material that can have Carbon, silver, and silver chloride are preferred from the viewpoint of printing.

In use, the electrode membrane of the first embodiment is attached to the administration site. In this case, it is preferable to adhere to the skin or mucous membrane. Next, a therapeutic agent is applied to the drug permeable membrane. Because the drug permeable membrane is porous, the therapeutic agent contacts the skin. An electrical signal is applied using electroporation so that the therapeutic agent is delivered through the skin.
Alternatively, the therapeutic agent may be impregnated in the drug permeable membrane before being applied to the administration site.

A second embodiment of the present invention (shown in FIG. 4) is an electroporation device incorporating the above-described electrode membrane. The adhesive layer 41 contains an adhesive for keeping the device in contact with skin and mucous membranes. An electrode membrane 42 for the electroporation method described above (shown in FIGS. 1 and 2) is at the bottom of the device. The drug component layer 43 contains a therapeutic drug to be administered. Casing 44 is a reservoir containing drug layer 43. The contact electrode pair (located inside the electrode film 42. The contact electrode pair 12 in FIGS.
22 (see FIG. 22) protrudes from the casing 44 for connection to a power supply (not shown).

In use, the device according to the second embodiment is glued to the administration site and held in place with an adhesive. The medicinal component may be already contained in the reservoir, or the medicinal component may be applied after bonding. As in the case of the first embodiment, the drug component or the therapeutic drug comes into contact with the administration site by penetrating the drug permeable membrane. By applying an electrical signal to the contact electrode using electroporation, the therapeutic agent is delivered.

A third embodiment of the present invention (shown in FIG. 3) is an apparatus that can use both electroporation and ion permeation. The adhesive layer 31 contains an adhesive for keeping the device in contact with skin and mucous membranes. The electrode membrane 32 for the electroporation described above (shown in FIGS. 1 and 2) is at the bottom of the device. The drug component layer 33 contains a therapeutic drug to be administered. The casing 34 forms a reservoir containing the pharmaceutical ingredient layer 33. The contact electrode pair (located inside the contact electrode pair 32. The contact electrode pair 11 shown in FIGS.
, 22) protrude from the casing 34 for connection to a power supply device (not shown). The above components are similar to those of the second embodiment shown in FIG. 4, but the third embodiment has an electrode film 32 and a casing 3
4 is provided with an electrode (anode or cathode) 36 for ion permeation method. A reverse electrode (not shown) opposite to the ion permeation electrode (ie, if the ion permeation electrode 36 is an anode, the reverse electrode is a cathode) is also attached to the skin or mucous membrane, Complete electrical circuit.

In use, the device according to the third embodiment is glued to the administration site and held in place with an adhesive. The reservoir may already contain the medicinal component, or the medicinal component may be added after bonding. As in the case of the first embodiment, the drug component or the therapeutic agent comes into contact with the administration site by penetrating the drug-permeable membrane. An electric signal is applied to the contact electrode, another electric signal is applied to the ion permeation method electrode, and the therapeutic agent is delivered by using both the electroporation method and the ion permeation method.

The casings 33 and 34 (FIGS. 3 and 4 respectively)
It is desirable that the material 4 be made of a material that can be elastically deformed (has flexibility and shape retention) and has water resistance. For example, polyvinylidene chloride, polyvinyl chloride, polyolefin, polyester, polystyrene, polyacryl, polyamide, polyoxymethylene, polyphenylene sulfonamide, polyamide,
Polyimide, polyacrylonitrile, polyetherketone, polyethersulfone, polysulfone, etherimide, polybutadiene, isoprene, and copolymers of these materials may be used, but the present invention is not limited thereto.
The casing is desirably in the form of a film (for example, a backing film or the like) or made of the above-mentioned material formed in a specific shape. Although the thickness is not particularly limited, a preferable shape retention force and flexibility can be obtained if the thickness is about 5 mm to 250 mm.

[0021] The administered pharmaceutical ingredient delivered by the device includes an ingredient that provides the desired biological effect. The components are contained in the pharmaceutical component layers 33 and 34, and preferably, besides the base components (therapeutic agents, etc.), electrolytes, absorption enhancers, stabilizers, pH
It preferably contains a buffer, a thickener, a surfactant, an emulsifier, an ion-exchange resin, an ion-exchange membrane, or a nonwoven fabric, but components contained in addition to the base component are not limited to these.

It is desirable that the casings 35 and 45 and the electrode films 32 and 42 are sealed using a method such as heat sealing.

When the ion permeation electrode 36 (anode or cathode) is incorporated, the ion permeation electrode 36 may be a polarizing electrode made of a material such as carbon, platinum, gold, or titanium. An unpolarized electrode may be used, but an unpolarized electrode is preferred. The unpolarized anode electrode preferably contains silver or copper as much as possible, but silver is more preferable. Preferably, the unpolarized cathode electrode contains silver chloride or copper chloride as much as possible, but silver chloride is more preferred.

Regarding the electroporation method, an electric signal is applied to the contact electrode so that the contact voltage is 10 V / cm to 20 V / cm.
A voltage difference in the range of 00 V / cm is generated. 50V / cm-1000V /
cm, more preferably about 50 V / cm to 500 V / cm. Recommended electric signal application patterns include, but are not limited to, exponential logarithmic waveforms and rectangular waveforms. Preferably, the electrical signal for electroporation is applied one or more times.

In the ion permeation method, an electric signal is applied to an electrode pair for ion permeation method (the electrode 36 for ion permeation method and the opposite electrode in FIG. 3). The signal to be applied should be 0.01
A pulse current signal of about mA to 10 mA is preferable, and a pulse current signal of about 0.01 mA to 5 mA is more preferable. A voltage difference occurs, and the voltage difference is preferably 0.1 V to 5 V.
It is preferably about 0 V, more preferably about 1 V to 30 V, and still more preferably about 3 V to 15 V. The pulse current signal has a pulse depolarization frequency, preferably about 100 Hz to 1000 kHz, more preferably about 1 kHz to 500 kHz, and more preferably about 10 kHz to 300 kHz. The duty cycle of the current signal is preferably about 1% to 99% if possible, more preferably about 10% to 80%, and more preferably about 15% to 50%. The waveform when applying current, DC, pulse, or pulse depolarization may be freely set.

As noted above, the pharmaceutical ingredients preferably include a therapeutic agent (such as a biologically active agent) to achieve the desired therapeutic effect at delivery (eg, to ameliorate any disorder). Is preferred. The type of therapeutic agent used in the present invention is not limited. Examples include morphine, fentanyl, meperidine, codeine, analgesics such as buprenorphine, butorphanol, eptazosin, or pentazocine, insulin, peptides related to calcitonin gene, vasopressin, desmopredin, proteinirin (TRH), adrenocorticotropic hormone (TRH)
ACTH), luteinizing hormone releasing hormone (LH-RH), growth hormone releasing hormone (GRH), nerve growth factor (NGF) or other releasing factors, angiotensin, parathyroid hormone (PTH), thyroid stimulating hormone (TSH, thyrotropin) ), Follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, serum gonadotropin, chorionic gonadotropin (HCG), human menopause gonadotropin (HMG), human growth hormone, somatostatin, somatomedin,
Glucagon, oxytocin, gastrin, secretin, endorphin, enkephalin, endothelin, cholecystokinin, neurotensin, interferon, interleukin, transferrin, erythropoietin (EPO), superoxide dismutase (SOD), granule cell stimulating factor (G-CSF) )
Peptides such as, for example, vasoactive intestinal peptide (VIP), muramyl dipeptide, urogastron, or human atrial natriuretic peptide (h-ANP) /
Tranquilizers such as protein, carbamazepine, chlorpromazine, diazepam or nitrazepam; antineoplastic agents such as pleomycin, doxorubicin, 5-fluorouracil or mitomycin; inotropic drugs such as digitalis and digitoxin; sex hormones such as estradiol and testosterone; or blood pressure such as reserpine and clonidine. Drugs, including, but not limited to, antihypertensive drugs. In addition, oligonucleotides such as antisense DNA and triple helix forming oligonucleotides can also be used.

Using the techniques described above, the present invention effectively delivers therapeutic agents through the skin and mucous membranes. In conventional electroporation electrodes, the electrode pair is usually attached to a film that is impermeable to the substance. It has been common practice to apply a drug solution to a site such as the skin, place an electrode film above the site, and apply an electric field pulse. If multiple dosings were required, the procedure had to be repeated and could not be performed in a single operation. When the ion permeation method is used together, the drug solution is applied to the administration site, and then the site is covered with an electrode film. After performing the electroporation method, after removing the electrode film, an electrode for ion permeation method was usually attached to the site, and a current for ion permeation was usually applied. This operation had to be performed step by step. If another electroporation is performed, the procedure is repeated. This procedure could not be completed by only attaching the electrode once.

The present invention not only allows the administration of the therapeutic agent with a single application of the device containing the electrode membrane, but also allows for continuous administration. Even when used in combination with the ion permeation method, it is only necessary to attach the electrode membrane (for the electroporation method) and an apparatus incorporating the electrode for the ion permeation method once. Further, once the electrodes are attached, the electroporation method and the ion permeation method can be performed as many times as necessary. Therefore, by using the device according to the present invention, the electroporation method can be performed alone, the electroporation method and the ion permeation method can be performed together, and the device can be used for multiple administrations over a long period of time. A device is provided that can. The invention can be used for the administration of therapeutic agents widely throughout the medical field.

In the following, examples of the present invention are presented to illustrate the use and effect of the present invention,
The present invention is not limited to the following format.

In Experimental Example 1, the administration of sodium benzoate was performed using the electrode pair of the prior art, using the electrode membrane according to the present invention, and using the electrode membrane according to the present invention. Compare the ease of administration with the device. Compliance was compared using the number of operations as an indicator.

In Experimental Example 1-1, the electrode film according to the present invention was used. The electrode film is made of Durap
ore SVLP ^™ membrane (manufactured by Millipore ^™ ; pore diameter = 3.0 mm) (
1 and 2) and a silver electrode pair. An adhesive was applied to the outer periphery, and the electrode film was attached to the skin. The drug (aqueous solution of sodium benzoate, 100 mg / ml) on the electrode membrane was administered at 200 ml / h for 3 hours (total 600 ml). Each time the drug solution was administered, an electric field pulse of 200 V / cm was applied from a power supply for electroporation (BTX ^™ ). Counted the number of operations.

In Experimental Example 1-2, an apparatus including the electrode film according to the present invention was used. The device shown in FIG. 4 was manufactured using the electrode film described in Experimental Example 1-1. The device contained 600 ml of drug solution. The device containing this electrode was attached to the skin, and every hour, 200 V / cm from a power supply for electroporation (manufactured by BTX ^™ )
Was applied. Counted the number of operations.

In Comparative Example 1, a prior art electrode film was used. Electrode films currently commercially available (BTX ^TM manufactured BT454-2P ^TM) was used. A solution of the drug (aqueous solution of sodium benzoate, 100 mg / ml) was applied to the skin and the part was covered with an electrode film. 200V / c from the power supply for electroporation (BTX ^TM )
The number of operations was counted by applying m electric field pulses.

The results of Experimental Example 1 are as shown in FIG. When the electrode film according to the present invention was used (Experimental Example 1-1), a total of seven operations were required. The contents are as follows. (1) Attach electrodes. (2) Apply the drug solution. (3)
After applying the voltage, wait until one hour elapses. (4) Apply the drug solution. (
5) After applying the voltage, wait until one hour elapses. (6) Apply a solution of the drug. (7) Apply voltage.

When the device including the electrode film according to the present invention was used (Experimental example 1-2), a total of four operations were required. The contents are as follows. (1) Attach the device. (2) After applying the voltage, wait until one hour elapses. (3) After applying the voltage, wait until one hour elapses. (4) Apply voltage.

When using a prior art electrode film and administering it using conventional methods (
Comparative Example 1) required a total of 11 operations. The contents are as follows. (1) Apply a drug solution. (2) Attach electrodes. (3) After applying the voltage, wait until one hour elapses. (4) Strip the electrode. (5) Apply the drug solution. (6) Attach electrodes. (7) After applying the voltage, wait until one hour elapses. (8) Strip the electrode. (9) Apply the drug solution. (10) Attach electrodes. (11) Apply voltage.

As can be seen from the number of operations described above, the use of the electrode membrane according to the invention simplifies the administration. Considering actual applications, when a patient administers a therapeutic drug at home, the administration form of Comparative Example 1 is not practical. On the other hand, if the device as in Experimental Example 1-2 is used, the patient can easily administer the drug at home.

In Experimental Example 2, when administering an aqueous solution of lidocaine hydrochloride using both the electroporation method and the ion permeation method, administration was performed using the electrode membrane according to the present invention and the conventional electrode film. Compare ease of use. Using the number of operations as a metric,
Compliance was compared.

In Experimental Example 2-1, a 200-ml lidocaine hydrochloride aqueous solution (200 ml of an aqueous solution of lidocaine hydrochloride (tansQ ^™ manufactured by Iomed ^™ ) was added to an apparatus containing a commercially available electrode for iontophoresis (tansQ ^™ manufactured by Iomed ^™ ).
5%). The apparatus was manufactured by incorporating the electrode for ion permeation method and the electrode membrane according to the present invention prepared in Experimental Example 1-1 as shown in FIG. The device was attached to the skin with a reverse electrode (tansQ ^™ from Iomed ^™ ). The iontophoresis electrode pair (the anode is on the drug side of the administration site and the cathode is the reverse electrode) was connected to the iontophoresis power supply. A voltage of 200 V / cm was applied from the power supply for electroporation, and then 0.1 hour from the power supply for ion permeation for 1 hour under the same conditions.
mA / cm2 was applied. Counted the number of operations.

In Experimental Example 2-2, the same operation as in Experimental Example 2-1 was performed. However, the start time and the stop time of the application of the electric signal for the application time for the ion permeation method and the application time for the electroporation method were first set in a timer, and the start and stop were automatically performed. The number of operations was counted.

In Comparative Example 2, 200 ml of an aqueous solution of lidocaine hydrochloride (5%) was added to a commercially available device containing an electrode for ion permeation (tansQ ^™ from Iomed ^™ ). Electroporation was performed on the skin (at 200 V / cm) using conventional electrode pairs.
An iontophoresis device containing lidocaine was attached to the skin and current was applied for one hour. After 1 hour, electroporation was performed, and then ion permeation was performed again for 1 hour. Counted the number of operations.

The results of Experimental Example 2 are as shown in FIG. In Experimental Example 2-1, a total of five operations were required. The contents are as follows. (1) Attach the device. (2) Apply voltage for electroporation. (3) Apply a current for the ion infiltration method. (4) Apply voltage for electroporation. Then, (5) a current for the ion permeation method is applied.

In Experimental Example 2-2, since the application of the voltage for electroporation and the current for ion permeation in Experimental Example 2-1 can be performed automatically using a timer, the number of operations is small. It only needed to be operated once (attached the device).

On the other hand, in Comparative Example 2, a total of 11 operations were required. The contents are as follows. (1) Attach the electrode film. (2) Apply voltage for electroporation. (3) Remove the electrode for electroporation. (4) Attach an ion infiltration device containing lidocaine. (5) Apply a current for the ion infiltration method. (6
) Remove the iontophoresis device containing lidocaine. (7) Attach the electrode film. (8) Apply voltage for electroporation. (9) Remove the electrode for electroporation. (10) Attach an ion infiltration device containing lidocaine. (11
) Apply current for ion permeation method.

The effect of promoting absorption of a therapeutic agent through the skin and mucous membranes has been described above. In Experimental Example 3, the effect of electroporation on insulin absorption when the electrode membrane according to the present invention and insulin were used was studied, which will be described below.

To produce an electrode for electroporation, as shown in FIG. 7, a polyvinylidene fluoride (Millipore, Hydrophilic) forming a membrane piece 700 is formed.
A carbon ink 705 was imprinted on a porous film 710 having a pore diameter of 5.0 microns (Durapore or the like). Before conducting the experiment, a portion of the resulting film piece was cut into the shape of the electrode film 800 shown in FIG. In this configuration, the anode connection 805 and the cathode connection 810 protrude from either side.

FIG. 9 shows a pharmaceutical device or “donor device” for administering a therapeutic agent. To make the donor device, an electrode cup 900 was formed by adding a silver or silver chloride electrode to the cup 910 as shown in FIG. Electrode 905
Terminal 915 protrudes from the side surface of the cup 910, and is connected to a pulse generator (not shown) for iontophoresis. Cup 910 has a rim 920 to support the attached membrane. This will be described later. Powder agar is suspended in water. This suspension was heated to about 70 ° C. in order to melt the agar and form a 1.5% aqueous agar solution. This solution was poured into the electrode cup 900, and the agar solution was cured at room temperature. This electrode cup containing the agar gel is the donor device.

FIGS. 10A and 10B are a perspective view and a side view, respectively, of the reference electrode 1000 for ion permeation method. A silver electrode 1005 was mounted on a polyethylene terephthalate film 1010 in order to form a reference electrode 1000 for an ion permeation method. Using a layer of polyurethane 1015, outline the edge of silver electrode 1005 and place compartment 102 over the electrode.
0 was formed. The wall of the compartment 1020 forms a recess for containing a liquid. The previously prepared 12% aqueous solution 1025 of polyvinyl alcohol (containing sodium chloride) was poured into compartment 1020. Solution 1025 to -80
Cur to a gel at ℃.

The appropriate dose of insulin was estimated by weight in a silicon-coated tube. Phosphoric acid, acetic acid and boric acid (each at a concentration of about 1 / 25M) were combined. This mixture was added to insulin. The mixture was swirled for 2-3 seconds to dissolve the insulin. An aqueous solution of 4% calf serum albumin and 28% urea was added to the mixture. An aqueous solution of sodium hydroxide (about 2M) was added to the mixture to adjust the pH to about 7.0. The final concentration of insulin in this solution was about 500 IU / ml (1 mg is about 28 IU). This solution is
Called "donor solution".

FIG. 11 shows an in vivo percutaneous absorption experiment for measuring insulin absorption. The abdomen of SD rat 1105 (7 weeks old) was sliced. Electrode film 11
10 was mounted along the rim 1112 of the donor device 1115 and contacted the agar gel in the electrode cup. About 40 ml of the donor solution containing insulin was placed on the opposite side of the electrode membrane 1110 from the agar gel. The donor device 1115 attached to the electrode membrane 1110 was placed on the rat 1105 so that the donor solution on the electrode membrane 1110 was in direct contact with the sliced portion of the rat 1105. The ion permeation reference electrode 1120 was also placed in another part of the sliced part of the rat 1105.
The code coming from the electroporation pulse generator 1125 was fixed to the anode and cathode connections 1127 and 1128 of the electrode membrane 1110, respectively. The reference electrode 1120 was connected to the positive terminal 1130 of the pulse generator 1135 for ion permeation method. The negative terminal 1140 of the ion permeation pulse generator 1135 was connected to the silver / silver chloride electrode terminal 1142 of the donor device 1115.

Immediately after the start of the experiment, about 200 V from the electroporation pulse generator was applied at a rate of 10 milliseconds per pulse for about 15 minutes (about 693 pulses). At the same time, a direct current of about 0.4 mA was simultaneously applied from the pulse generator 1135 for the ion permeation method. Therefore, both iontophoresis and electroporation were performed during this first 15 minutes. Thereafter, only the application of the ion penetration method was continued for about 45 minutes. Eventually, blood was drawn from the jugular vein of rat 1105. After heparin treatment, E
Plasma was analyzed using a LISA kit, a DSL human insulin kit for measuring human insulin.

In Comparative Example 3, the same procedure as in Experimental Example 3 was followed, but in Comparative Example 3, only the ion infiltration method was employed. The preparation of the donor device, the ion penetration reference electrode, the donor solution, and the plasma analysis were the same as those in Experimental Example 3.

In Comparative Example 3, the measurement of absorption was the same as in Experimental Example 3. Although the arrangement of the components was the same as that shown in FIG. 11, the electroporation method was not used in Comparative Example 3, so that the electrode film, the pulse generator for electroporation, or the electric power for electroporation were used. Connection is not included.

The abdomen of SD rats (7 weeks old) was sliced. A porous membrane was attached along the rim of the donor device and brought into contact with the agar gel in the electrode cup. About 40 ml of the donor solution containing insulin was placed on the opposite side of the porous membrane from the agar gel. The donor device attached to the porous membrane was placed on the rat so that the donor solution on the porous membrane was in direct contact with the rat slices. Both the ion-permeation reference electrode and the ion-permeation reference electrode were placed elsewhere in the sliced part of the rat. The reference electrode was connected to the positive terminal of the pulse generator for iontophoresis. The negative terminal of the pulse generator for iontophoresis was connected to the silver / silver chloride electrode terminal of the donor device. A direct current of about 0.4 mA was applied from a pulse generator for an ion permeation method. About 6 more ion permeation applications
Continued for 0 minutes. Eventually, blood was drawn from the jugular vein of rat 1105. After heparin treatment, plasma was analyzed using an ELISA kit and a DSL human insulin kit for measuring human insulin.

FIG. 12 shows the relationship between insulin concentration and time in plasma obtained from rats obtained from both Experimental Example 3 and Comparative Example 3. Curve 1205 shows the concentration resulting from the use of iontophoresis and electroporation according to the present invention. Curve 1210 shows the concentration that results when using iontophoresis alone. This graph shows that the amount of insulin absorbed was about 811 microIU / ml · min by using the ion permeation method and the electroporation method described in Experimental Example 3. It is indicated by the area under the curve 1205 from 0 minutes to 120 minutes. On the other hand, when the technique described in Comparative Example 3 was used (the electrode membrane according to the present invention was not used), the amount of insulin absorbed was about 208 microIU / ml · min, which was an experimental example. The result was about one-fourth of the result of No. 3.

In performing these calculations, before placing the membrane and donor device on the rat, a concentration was first measured that showed an intensity equal to the background intensity of insulin in the plasma of the rat. The concentration at each time point was determined by subtracting the concentration showing an intensity equal to this background intensity from the measured concentration at that time point.

These examples clearly show that an electrode membrane that administers a therapeutic agent such as insulin using both electroporation and iontophoresis according to the present invention is effective. Furthermore, the improved dosing by using both electroporation and iontophoresis indicates that the method and apparatus are more effective than using iontophoresis alone. From the results of Experimental Example 3 and Comparative Example 3, the osmotic electrode membrane device including both the electrode for electroporation and the electrode for ion osmosis is more effective than insulin osmosis alone for treating insulin-like treatment. It is clear that it is effective for the delivery of drugs.

As described above, the device according to the present invention incorporates both the electrode membrane for electroporation and the electrode for ion permeation into a single device, and uses both electroporation and ion permeation. Be able to provide equipment. In the existing technology related to the combination of the electroporation method and the ion permeation method, generally, a plurality of times such as attaching the electrode for the electroporation method, removing the electrode, and then attaching the electrode for the ion penetration method to the same site. Cruising is required. This procedure is generally not practical. The use of the present invention eliminates the need to remove the electroporation electrode from the attachment site each time the therapeutic agent is administered. Once the electrode membrane is attached, the therapeutic agent can be administered as many times as possible, or the therapeutic agent can be administered continuously over a long period of time. Thus, the present invention applies iontophoresis and electroporation simultaneously from a single device without multiple attachments.

The embodiments of the present invention have been described above. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Therefore, embodiments other than the above are also included in the following claims.

Similar reference numerals and designations used in the drawings (FIGS. 1-12) indicate similar components.

[Brief description of the drawings]

FIG. 1 is a side view of an apparatus according to a first embodiment of the present invention.

FIG. 2 is a plan view of the device according to the first embodiment of the present invention.

FIG. 3 is a plan view of an apparatus according to a third embodiment of the present invention that uses both electroporation and ion permeation.

FIG. 4 is a diagram showing a second embodiment of the present invention.

FIG. 5 shows three different application examples of the electroporation method (Experimental example 1-2, Experimental example 1-1, Comparative example 1).
6 is a graph showing a comparison of the number of operations obtained from FIG.

FIG. 6 shows an application example in which an electroporation method and an ion permeation method are used together (Experimental example 2-2, Experimental example 2-1,
9 is a graph showing a comparison of the number of operations obtained from Comparative Example 2).

FIG. 7 is a view showing a film piece according to the present invention.

FIG. 8 is a view showing an electrode film according to the present invention.

FIG. 9 illustrates a pharmaceutical device or “donor device” for administering a therapeutic agent.

FIG. 10A is a perspective view of an ion permeation method reference electrode.

FIG. 10B is a side view of an ion permeation method reference electrode.

FIG. 11 is a diagram showing an in vivo percutaneous absorption experiment for measuring insulin absorption.

FIG. 12 is a graph showing the relationship between insulin concentration of plasma obtained from rats and time.

Claims (55)

[Claims] 1. A device for administering a therapeutic agent comprising a drug permeable membrane having a pair of contact electrodes, wherein the drug permeable membrane is directly connected to the administration site when the device is brought into contact with the administration site. A device adapted to contact the device. 2. The device of claim 1, wherein the drug permeable membrane has a diameter of about 0 mm.
. An apparatus characterized in that it has a pore of 01 mm to 10 mm. 3. The device according to claim 2, wherein the drug permeable membrane has a diameter of about 0 mm.
. An apparatus characterized by having pores of 1 mm to 5 mm. 4. The device of claim 1, wherein the drug permeable membrane is made of one or more materials having a permeability matched to the permeability properties of the therapeutic agent. Equipment to do. 5. The device according to claim 1, wherein the drug permeable membrane is made of nylon, polyvinylidene fluoride, cellulose, nitrocellulose, polycarbonate,
A device selected from the group consisting of polysulfone, polyethylene, polypropylene, nonwoven fabric, gauze, woven fabric, paper, cotton fabric, expanded polyethylene, expanded polypropylene, expanded polyvinyl acetate, expanded polyolefin, expanded polyamide, and expanded polyurethane. 6. The apparatus according to claim 1, wherein the contact electrodes are approximately one-to-one with each other.
An apparatus characterized by being separated from 0 mm to 1 cm. 7. The apparatus according to claim 6, wherein said contact electrodes are approximately 5
An apparatus characterized by being separated from 0 mm to 5 mm. 8. The apparatus according to claim 7, wherein the contact electrodes are about one-to-one with each other.
An apparatus characterized by being 2 mm apart from 00 mm. 9. The device according to claim 1, wherein the contact electrode is made of a metal or a semiconductor. 10. The apparatus according to claim 1, wherein said contact electrode is made of carbon, silver, or silver chloride. 11. The device according to claim 1, further comprising a casing attached to the drug permeable membrane. 12. The apparatus according to claim 11, wherein the casing is attached to the drug permeable membrane such that a reservoir is formed between the casing and the drug permeable membrane. And equipment. 13. The device according to claim 12, wherein the device is adapted to be attached to the skin or mucous membranes. 14. The device according to claim 12, wherein the casing is made of a material that is deformable with a resilience. 15. The apparatus according to claim 12, wherein said casing is made of a water-resistant material. 16. The apparatus according to claim 12, wherein said casing is made of a polymer or a copolymer. 17. The apparatus according to claim 12, wherein the casing is made of polyvinylidene chloride, polyvinyl chloride, polyolefin, polyester, polystyrene, polyacryl, polyamide, polyoxymethylene, polyphenylenesulfonamide, polyamide, polyimide, An apparatus made of at least one material selected from the group consisting of polyacrylonitrile, polyetherketone, polyethersulfone, polysulfone, etherimide, polybutadiene, and isoprene. 18. The apparatus according to claim 12, wherein said casing has a thickness of about 5 mm to 250 mm. 19. The device according to claim 12, further comprising a pharmaceutical component having a therapeutic agent, wherein the pharmaceutical component is contained in the reservoir. 20. The device according to claim 19, wherein the pharmaceutical component further comprises an electrolyte, an absorption enhancer, a stabilizer, a pH buffer, a thickener, a surfactant, an emulsifier, an ion exchange resin, an ion exchange. A device comprising one or more substances selected from the group consisting of a membrane or a nonwoven. 21. The device of claim 12, wherein the reservoir includes an iontophoresis electrode. 22. The apparatus according to claim 21, wherein the ion permeation electrode is a polarizing electrode made of a material selected from the group consisting of carbon, platinum, gold, and titanium. Equipment to do. 23. The apparatus according to claim 21, wherein the electrode for ion permeation is an unpolarized electrode. 24. The apparatus according to claim 23, wherein the ion permeation electrode is an anode containing copper. 25. The apparatus according to claim 23, wherein the ion permeation electrode is an anode containing silver. 26. The apparatus according to claim 23, wherein the ion permeation electrode is a cathode containing copper chloride. 27. The apparatus according to claim 23, wherein the electrode for iontophoresis is a cathode containing silver chloride. 28. The device of claim 1, wherein the therapeutic agent is from the group consisting of an analgesic, a peptide / protein, a tranquilizer, an antineoplastic, an inotropic, a hormone, a hypotensive, and a polynucleotide. A device characterized by one or more selected drugs. 29. The device according to claim 1, further comprising an adhesive layer on the drug permeable membrane in contact with the administration site. 30. The device of claim 12, wherein the casing is sealed to the drug permeable membrane using heat sealing. 31. (a) an adhesive layer; (b) a drug-permeable membrane attached to the adhesive layer; (c) a first electrode to which the drug-permeable membrane n is attached; A therapeutic agent; (e) one or more non-biologically active agents and a pharmaceutical ingredient containing the therapeutic agent; and (f) a casing forming a reservoir between the drug permeable membrane and the casing. An electrode membrane comprising: a casing in which the reservoir contains a pharmaceutical ingredient; and (g) a second electrode attached to the casing. 32. (a) contacting a device including a drug permeable membrane with a pair of contact electrodes with an administration site such that the drug permeable membrane is in direct contact with the administration site; and (b) A method of in vivo administering a therapeutic agent, comprising: applying a therapeutic agent to the drug permeable membrane; and (c) applying an electric signal to the contact electrode. 33. The method according to claim 32, wherein the contact electrode is for electroporation. 34. The method according to claim 33, wherein the electrical signal causes a voltage difference between the contact electrodes of between about 10 V / cm and 2000 V / cm. 35. The method according to claim 34, wherein the voltage difference is about 50 volts.
/ Cm to 1000 V / cm. 36. The method according to claim 35, wherein the voltage difference is about 50 volts.
/ Cm to 500 V / cm. 37. The method of claim 33, wherein the electrical signal is applied to the contact electrode in a rectangular waveform. 38. The method according to claim 33, wherein the electrical signal is applied to the contact electrode in an exponential logarithmic manner. 39. A method of in vivo administering a therapeutic agent, comprising: (a) a drug permeable membrane having a pair of contact electrodes; a casing attached to the drug permeable membrane forming a reservoir; Contacting a device containing a drug component containing a therapeutic agent with an administration site such that the drug permeable membrane is in direct contact with the administration site, wherein the drug component enters the reservoir. Placing an iontophoresis electrode in the reservoir; (b) contacting a reverse electrode with a second site; and (c) applying a first electrical signal to the contact electrode. And (d) applying a second electrical signal to the iontophoresis electrode. 40. The method of claim 39, wherein said second electrical signal is a pulsed current signal of about 0.01 mA to 10 mA. 41. The method of claim 40, wherein the pulsed current signal is a pulsed current signal of about 0.01 mA to 5 mA. 42. The method according to claim 39, wherein the second electrical signal causes a voltage difference between about 0.1V and 50V between the iontophoresis electrode and the counter electrode. And how to. 43. The method of claim 42, wherein said voltage difference is between about 1V and 30V. 44. The method of claim 43, wherein the voltage difference is between about 3V and 15V. 45. The method according to claim 39, wherein the second electrical signal is a pulse depolarized signal having a pulse frequency of about 100 Hz to 1000 kHz. 46. The method of claim 45, wherein the pulse frequency is between about 1 kHz and 500 kHz. 47. The method of claim 46, wherein said pulse frequency is between about 10 kHz and 300 kHz. 48. The method of claim 39, wherein the second electrical signal has a duty cycle with an on / off ratio of about 1% to 99%. 49. The method of claim 48, wherein said duty cycle is between about 10% and 80%. 50. The method of claim 49, wherein the duty cycle is between about 15% and 50%. 51. The device of claim 19, wherein the therapeutic agent is from the group consisting of analgesics, peptides / proteins, tranquilizers, antineoplastics, inotropics, hormones, hypotensives, and polynucleotides. A device characterized by one or more selected drugs. 52. The device of claim 12, further comprising an adhesive layer on the drug permeable membrane in contact with the administration site. 53. An apparatus for administering a therapeutic agent, comprising: an electrode cup including an electrode and a rim; and a rim of the electrode cup including a permeable membrane and a pair of electrodes engraved on the permeable membrane. An apparatus comprising: an attached electrode film. 54. The apparatus according to claim 53, wherein the electrodes of the electrode cup are connected to an iontophoresis generator. 55. The apparatus according to claim 53, wherein the electrodes of the electrode membrane are connected to an electroporation generator.